Retrograde labeling correlates with motor unit number estimation in rapid-stretch nerve injury.

INTRODUCTION/AIMS: Rapid-stretch nerve injuries represent a substantial treatment challenge. No study has examined motor neuron connection after rapid-stretch injury. Our objective in this study was to characterize the electrophysiological properties of graded rapid-stretch nerve injury and assess motor neuron health using retrograde labeling and muscle adenosine triphosphatase (ATPase) histology. METHODS: Male C57BL/6 mice (n = 6 per group) were rapid-stretch injured at four levels of severity: sham injury, stretch within elastic modulus, inelastic deformation, and stretch rupture. Serial compound muscle action potential (CMAP) and motor unit number estimation (MUNE) measurements were made for 48 days, followed by retrograde labeling and muscle ATPase histology. RESULTS: Elastic injuries showed no durable abnormalities. Inelastic injury demonstrated profound initial reduction in CMAP and MUNE (P < .036) on day 2, with partial recovery by day 14 after injury (CMAP: 40% baseline, P = .003; MUNE: 55% baseline, P = .033). However, at the experimental endpoint, CMAP had recovered to baseline with only limited improvement in MUNE. Inelastic injury led to reduced retrograde-labeled neurons and grouped fiber type histology. Rupture injury had severe and nonrecovering electrophysiological impairment, dramatically reducing labeled neurons (P = .005), and atrophic or type 1 muscle fibers. There was an excellent correlation between MUNE and retrograde-labeled tibial motor neurons across injury severities (R2  = 0.96). DISCUSSION: There was no significant electrophysiological derangement in low-severity injuries but there was recoverable conduction block in inelastic injury with slow recovery, potentially due to collateral sprouting. Rupture injuries yielded permanent failure of injured axons to reinnervate. These results provide insight into the pathophysiology of clinical injuries and recovery.

The motor unit and quantitative electromyography.

Electromyography (EMG) assesses the anatomic motor unit (A-MU), but knowledge of its anatomy, physiology, and changes with pathology is limited. The electrophysiological motor unit (E-MU) and its motor unit potential (E-MUP) represents a fraction of the A-MU. Routine EMG assesses a limited number of E-MUP waveform characteristics (metrics) and their magnitudes qualitatively scaled in a nonlinear manner. Another approach is quantitative EMG (QEMG), whereby 20+ E-MUPs are extracted and both basic and derived metrics obtained and values expressed quantitatively. In diseased muscle, many E-MUP metrics may be normal, which complicates diagnostic interpretation. In QEMG, E-MUP metrics can be clustered and statistical analyses performed to assign probabilities that E-MUPs (and the muscle) are normal, neuropathic, or myopathic. In this article we review what is known about the A-MU, the restricted E-MU, E-MUP metrics, and what QEMG offers currently and in the future.

Patient demographics and health plan paid costs in chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: We determined health plan paid costs and healthcare resource usage of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: CIDP patients from 9 U.S. commercial health plans with claims in 2011 were identified from the Accordant Health Services claims database. We examined demographics, prevalence of comorbidities, prescribed drugs, place of service, and mean annual health plan paid costs per patient. RESULTS: From 6.5 million covered lives, 73 (56% men; mean age 47) met study entry criteria. The most prescribed therapies were intravenous immunoglobulin (IVIg) (26% of patients), gabapentin (26%), and prednisone (16%). The annual health plan paid cost was $56,953. Pharmacy cost was the major cost driver (57% of the total), and IVIg totaled 90% of the pharmacy costs. CONCLUSIONS: Healthcare costs for CIDP patients are substantial, with a large burden in pharmacy usage. Studies are needed to determine optimal long-term treatment strategies for CIDP, particularly related to IVIg.

Motor unit number estimation: a technology and literature review.

INTRODUCTION: Numerous methods for motor unit number estimation (MUNE) have been developed. The objective of this article is to summarize and compare the major methods and the available data regarding their reproducibility, validity, application, refinement, and utility. METHODS: Using specified search criteria, a systematic review of the literature was performed. Reproducibility, normative data, application to specific diseases and conditions, technical refinements, and practicality were compiled into a comprehensive database and analyzed. RESULTS: The most commonly reported MUNE methods are the incremental, multiple-point stimulation, spike-triggered averaging, and statistical methods. All have established normative data sets and high reproducibility. MUNE provides quantitative assessments of motor neuron loss and has been applied successfully to the study of many clinical conditions, including amyotrophic lateral sclerosis and normal aging. CONCLUSIONS: MUNE is an important research technique in human subjects, providing important data regarding motor unit populations and motor unit loss over time.

What Is in the Literature.

ABSTRACT: This issue of What is in the Literature focuses on the Guillain-Barré syndrome. Guillain-Barré syndrome is a monophasic illness, and there is new information about precipitating factors, changes in nerve conduction studies over time, potential biomarkers, optimal treatment, and features in uncommon patient populations.

Preliminary Study on Effects of Neck Exoskeleton Structural Design in Patients With Amyotrophic Lateral Sclerosis.

Neck muscle weakness due to amyotrophic lateral sclerosis (ALS) can result in dropped head syndrome, adversely impacting the quality of life of those affected. Static neck collars are currently prescribed to hold the head in a fixed upright position. However, these braces are uncomfortable and do not allow any voluntary head-neck movements. By contrast, powered neck exoskeletons have the potential to enable head-neck movements. Our group has recently improved the mechanical structure of a state-of-the-art neck exoskeleton through a weighted optimization. To evaluate the effect of the structural changes, we conducted an experiment in which patients with ALS were asked to perform head-neck tracking tasks while using the two versions of the neck exoskeleton. We found that the neck muscle activation was significantly reduced when assisted by the structurally enhanced design compared to no assistance provided. The improved structure also improved kinematics tracking performance, allowing users to better achieve the desired head poses. In comparison, the previous design did not help reduce the muscle effort required to perform these tasks and even slightly worsened the kinematic tracking performance. It was also found that biomechanical benefits gained from using the structurally improved design were consistent across participants with both mild and severe neck weakness. Furthermore, we observed that participants preferred to use the powered neck exoskeletons to voluntarily move their heads and make eye contact during a conversation task rather than remain in a fixed upright position. Each of these findings highlights the importance of the structural design of neck exoskeletons in achieving desired biomechanical benefits and suggests that neck exoskeletons can be a viable method to improve the daily life of patients with ALS.

ALSUntangled #71: Nuedexta.

Nuedexta is a combination of dextromethorphan hydrobromide and quinidine sulfate and was approved by the Food and Drug Administration (FDA) in 2010 to treat pseudobulbar affect (PBA). There have since been anecdotal case reports of bulbar function improvements after Nuedexta treatment. Here, we review the off-label use of Nuedexta for improving bulbar function in people with ALS. Nuedexta has plausible mechanisms for protecting brain stem motor neurons via its effects on S1R and glutamate excitotoxicity. Recent clinical trials support that Nuedexta can improve bulbar function in PALS, with or without PBA. Nuedexta causes mild to moderate side effects. Based on this information, we support considering Nuedexta treatment for bulbar dysfunction in ALS patients with or without PBA.

ALSUntangled #73: Lion's Mane.

Lion's Mane (Hericium erinaceus) has historically been used as traditional medicine in Asia and Europe for its potential benefits in fighting infection and cancer. It has gained interest in the neurodegenerative disease field because of its mechanisms of action; these include anti-inflammation, neuroprotection, and promoting neurite growth demonstrated in various cell and animal models. A very small, double-blind, placebo-controlled trial in patients with mild cognitive impairment showed a temporary improvement in cognitive function; this finding has yet to be replicated. However, there have been no studies in ALS cell or animal models or in humans with ALS. Lion's Mane appears safe and inexpensive when consumed in powder or capsule, but one anaphylactic case was reported after a patient consumed fresh Lion's Mane mushroom. Currently, we do not have enough information to support the use of Lion's Mane for treating ALS. We support further research in ALS disease models and clinical trials to study its efficacy.

ALSUntangled #72: Insulin.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review insulin, which has at least one plausible mechanism for slowing ALS progression. However, pre-clinical studies are limited and there have been no trials in PALS yet. Insulin use in patients without a metabolic need may cause very serious and potentially lethal side effects. While further studies to evaluate potential benefits may be warranted, at this time we cannot endorse insulin treatment to slow ALS progression.

ALSUntangled #75: Portable neuromodulation stimulator therapy.

Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.

Quantitative electrodiagnosis of the motor unit.

Electromyography (EMG) focuses on assessment of the motor unit (MU), and a given muscle has several hundred MUs, each innervating hundreds of muscle fibers. Assessment is limited by the recording radius of electrodes, 1-2 fibers with single-fiber electrodes and 7-15 fibers with concentric or monopolar electrodes. Routine qualitative EMG studies rely on observing MUs in free-run mode and qualitatively estimating common metrics. In contrast, quantitative EMG (QEMG) applied to routine studies includes assessment of individual MUs by software available in modern EMG machines with extraction of discrete values for common metrics, and also derived metrics. This results in greater precision and statistical interpretation. Other QEMG techniques assess muscle fiber density within the MU and time variability at the neuromuscular junction. The interference pattern can also be assessed. The number of MUs innervating a muscle can be estimated. Advanced signal processing, called near-fiber EMG, allows for extraction of underlying muscle fiber contributions to MU waveforms. It is also possible to use QEMG to make statistical probabilities of the state of a muscle as to whether normal, myopathic, or neuropathic. Time to acquire QEMG data is minimal. QEMG is most useful in situations where pathology is uncertain.

ALSUntangled #66: antimycobacterial antibiotics.

Several infections have been associated with motor neuron diseases resembling ALS, including species of viruses, bacteria, and parasites. Mycobacterium avium subspecies paratuberculosis (MAP), most known for its probable etiologic association with Crohn's disease, has been suggested as another possible infectious cause of motor neuron disease. Two published case reports describe the successful treatment of ALS-like symptoms with antimycobacterial antibiotics. Both cases had atypical features. Based on these, we believe it would be reasonable to begin performing chest imaging in PALS who have features of their history or exam that are atypical for ALS such as pain, fevers, or eye movement abnormalities. If the chest imaging is abnormal, more specific testing for mycobacteria may be indicated. Until there is more clear evidence of an association between mycobacteria and ALS, we cannot endorse the widespread use of potentially toxic antimycobacterial antibiotics for PALS.

ALSUntangled #68: ozone therapy.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review ozone therapy. Ozone therapy has possible mechanisms for slowing ALS progression based on its antioxidant, anti-inflammatory, and mitochondrial effects. A non-peer-reviewed report suggests that ozone treatment may slow progression in a mTDP-43 mouse model of ALS. One verified "ALS reversal" occurred on a cocktail of alternative treatments including ozone. There are no ALS trials using ozone to treat PALS. There can be potentially serious side effects associated with ozone therapy, depending on the dose. Based on the above information, we support an investigation of ozone therapy in ALS cell or animal models but cannot yet recommend it as a treatment in PALS.

ALSUntangled #65: glucocorticoid corticosteroids.

ALSUntangled reviews alternative and off-label treatments for people with amyotrophic lateral sclerosis (PALS). Here we review glucocorticoids. Neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis, so some hypothesize that glucocorticoids might be an effective ALS therapy through their immunosuppressive effects. In this paper, we review the available evidence for glucocorticoids in ALS, including one pre-clinical study with a genetic mouse model of ALS, nine case reports (ranging from 1 to 26 patients each), and four clinical trials. We also review the possible side effects (including steroid myopathy) and the costs of therapy. We graded the level of evidence as follows: Mechanism, D; Pre-Clinical, F; Cases, B; Trials, F; Risks, C. Our review of the current evidence concludes that glucocorticoids do not offer clinical benefit in ALS and confer serious risks. Thus, ALSUntangled does not recommend glucocorticoids as a treatment for ALS.

ALSUntangled # 69: astaxanthin.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review astaxanthin which has plausible mechanisms for slowing ALS progression including antioxidant, anti-inflammatory, and anti-apoptotic effects. While there are no ALS-specific pre-clinical studies, one verified "ALS reversal" occurred in a person using a combination of alternative therapies which included astaxanthin. There have been no trials of astaxanthin in people living with ALS. Natural astaxanthin appears to be safe and inexpensive. Based on the above information, we support further pre-clinical and/or clinical trials of astaxanthin in disease models and PALS, respectively, to further elucidate efficacy.

ALSUntangled #63: ketogenic diets.

ALSUntangled reviews alternative and off label treatments with a goal of helping patients make more informed decisions about them. Here we review ketogenic diets. We shows that these have plausible mechanisms, including augmenting cellular energy balance and reducing excitotoxicity, neuroinflammation and oxidative stress. We review a mouse model study, anecdotal reports and trials in ALS and other diseases. We conclude that there is yet not enough data to recommend ketogenic diets for patients with ALS, especially in light of the many side effects these can have.

ALSUntangled #67: rituximab.

ALSUntangled reviews alternative and off-label treatments on behalf of people with ALS who ask about them. Here we review rituximab, a drug which specifically depletes B lymphocytes. We show a current lack of evidence for a role of these cells in ALS progression. The one patient we found who described using Rituximab for their ALS found no benefit. Given all this, and the known serious risks of rituximab, we advise against its use as an ALS treatment.

ALSUntangled #70: caffeine.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here, we review caffeine which has plausible mechanisms for slowing ALS progression. However, pre-clinical studies are contradictory, and a large case series showed no relationship between caffeine intake and ALS progression rate. While low doses of caffeine are safe and inexpensive, higher doses can cause serious side effects. At this time, we cannot endorse caffeine as a treatment to slow ALS progression.

Adult-onset lower extremity weakness caused by venous malformation detected by magnetic resonance imaging.

INTRODUCTION: Symptomatic venous malformation (VM) of muscle in adults is rare and usually presents in childhood or adolescence as the individual is growing. We describe an atypical presentation of a malformation affecting the gastrocnemius muscle asymmetrically with onset in adulthood, which created a diagnostic challenge. Electromyography (EMG) and muscle biopsy did not fit clinically and MRI of the gastrocnemius led to the diagnosis. METHODS: The setting for the patient studied was a neuromuscular outpatient clinic. RESULTS: EMG showed decreased insertional activity and motor unit potential recruitment in the right gastrocnemius muscle. Muscle biopsy showed mild neurogenic changes. MRI demonstrated VM in the contralateral gastrocnemius muscle. CONCLUSIONS: This case represents a rare cause of atrophic weakness in adults, but muscle MRI should be considered when other tests are equivocal.

The role of a clinical pharmacist in a multidisciplinary amyotrophic lateral sclerosis clinic.

Patients with ALS have complicated medication regimens and many questions about medications. Our multidisciplinary ALS clinic includes a clinical pharmacist, and the purpose of this study was to assess the types and outcomes of consultative interactions. This was a prospective, data collection study of patients seen by the pharmacist at a single ALS clinic visit. The following data were obtained: 1) current medications; 2) number and types of pharmacy interventions; 3) amount of time spent by the pharmacist with each patient. Thirty-seven patients were included. The average number of prescriptions used per patient was 3.59 (0-10) with 1.75 (0-9) used for ALS related indications. The average number of pharmacist interventions was two per patient, with the majority related to medication monitoring and optimizing drug therapy for ALS symptoms. The pharmacist provided education on an average of 2.5 topics per patient. The pharmacist spent an average of 21 (5-50) min with each patient. In conclusion, a clinical pharmacist contributes to the team by: 1) optimizing drug therapy for ALS symptoms; 2) providing medication-related education to patients; 3) allowing more time for the neurologist to attend to neurologic issues; and 4) discussing general medicine issues.